Angiogenesis, the development of new blood vessels, is a complex biological process which occurs both in physiological conditions, such as during embryonic development, wound healing etc., and in pathological conditions, such as cancer (Bikfalvi and Bicknel, 2002). Angiogenesis is controlled by the net balance between pro-angiogenic and anti-angiogenic factors. Known factors for promoting angiogenesis are for example the fibroblast growth factor (FGF) family, Vascular Endothelial Growth Factor (VEGF), Platelet-Derived Growth Factor (PDGF) and the angiopoetins. Factors which inhibit angiogenesis have been the focus of many anti-cancer research projects since it was postulated that tumors need to be vascularised in order to grow and that diffusible molecules regulate this process (see for example Auguste et al., 2005 for review). Anti-angiogenic molecules include antibodies such as avastatin, small chemical molecules, and endogenous factors, among which Platelet Factor 4 (PF4).
The CXC-chemokine family consists of pro-inflammatory cytokines, primarily involved in chemoattraction and activation of specific leukocytes in various immuno-inflammatory responses. The CXC chemokine family is unique because it comprises angiogenic and angiostatic chemokines. The Platelet Factor 4 (PF4 or CXCL4) was the first chemokine described as a regulator of angiogenesis (Maione T E et al. 1990). PF4 was previously known as oncostatin as described in the international patent application WO 85/04397.
At the same time, the gene of a nonallelic PF4-variant, called PF4v1 or CXCL4L1 was also identified. The mature proteins differ in only three amino acids located in the C-terminus (P58L, K66E, and L67H) in PF4 and PF4v1, respectively (Eisman R et al. 1990). PF4v1 was characterised as a potent inhibitor of angiogenesis more effective than PF4. Thus, the international patent application WO 2006/029487 relates to PF4v1, fragments, and modified versions of PF4v1 and PF4v1 fragments for the prevention and/or reduction of angiogenesis, and more particularly for the treatment or prevention of angiogenic disorders or diseases involving angiogenic disorders or pathological angiogenesis such as cancer.
In contrast to the many studies focused on the search for anti-angiogenic compounds, very few approaches have been developed to induce angiogenesis. Therefore, there is still a need in the art for methods for inducing angiogenesis.